Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar Rats via Their Modulatory Effects on Inflammation, Oxidative Stress, Apoptosis, and Nrf2

Ahmed, Osama M.; Elkomy, Mohammed H.; Fahim, Hanaa I.; Ashour, Mohamed B.; Naguib, Ibrahim A.; Alghamdi, Badrah S.; Mahmoud, Heba Uallah R.; Ahmed, Noha A.

doi:10.1155/2022/2710607

Cited by 36 publications

(25 citation statements)

References 82 publications

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“…According to our ndings, the administration of DOX elevated levels of these serum hepatic enzymes which indicated massive liver damage [5]. These results are in agreement with the results of several previous studies which demonstrated the destructive effects of DOX on the liver [24,25]. Our results showed that the use of metformin in DOX intoxicated rats signi cantly decreased the plasma enzyme levels compared to the DOX group.…”

Section: Discussionsupporting

confidence: 92%

Protective effects of metformin against doxorubicin-induced hepatoxicity in rats

lal-Shahsavar,

Zolbanin,

Jafari

et al. 2023

Preprint

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Purpose Doxorubicin (DOX) is one of the most commonly prescribed anti-cancer drugs. However, DOX-induced hepatotoxicity is a dose-limiting side effect. This study aimed to clarify the potential protective effects of metformin on DOX-induced hepatotoxicity in rats. Methods The animals were divided into six groups (n=6 each): Control Group, DOX group, metformin 200 mg/kg group, DOX + metformin 50 mg/kg group, DOX + metformin 100 mg/kg group, and DOX + metformin 200 mg/kg group. Hepatic injury was induced by a single intraperitoneal injection of DOX (20mg/kg). The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in serum were determined. Furthermore, the hepatic histopathological changes were evaluated. In order to identify the markers of oxidative stress, the level of malondialdehyde (MDA) and the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in liver tissue were measured. Results Results showed that DOX provoked a marked elevation in ALT, AST, and ALP serum levels. In addition, oxidative stress was significantly boosted in DOX-treated rats compared to control rats. All these were abolished with the metformin administration. Histological examination also showed that metformin could significantly reduce DOX-induced alterations. The most prominent effect was observed by high-dose metformin. Conclusion This study showed that metformin could prevent doxorubicin-induced hepatoxicity.

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Section: Discussionsupporting

confidence: 92%

Protective effects of metformin against doxorubicin-induced hepatoxicity in rats

lal-Shahsavar,

Zolbanin,

Jafari

et al. 2023

Preprint

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“…Nrf2 is a key modulator of cellular defense that counteracts the damage caused by oxidative stress [ 81 ]. It activates the basal and induced expressions of antioxidant response element (ARE)-dependent genes to control the physiological and pathophysiological outcomes of oxidant exposure ( Figure 12 ) [ 82 , 83 , 84 ]. Thus, Nrf2 is a cyto-protective transcription factor involved in antioxidant and anti-inflammatory pathways in addition to its ability to prevent mitochondrial degradation by interacting with ARE ( Figure 12 ) [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

Diosmin and Trolox Have Anti-Arthritic, Anti-Inflammatory and Antioxidant Potencies in Complete Freund’s Adjuvant-Induced Arthritic Male Wistar Rats: Roles of NF-κB, iNOS, Nrf2 and MMPs

et al. 2022

Self Cite

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Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease caused by a malfunction of the immune system. The aim of this study was to examine the anti-arthritic effects and suggest the mechanisms of actions of diosmin and trolox in male Wistar rats. Complete Freund’s adjuvant (CFA) was used to establish RA in the animals by subcutaneous injection of 100 µL CFA/rat into plantar region of right hind leg in two consecutive days. Diosmin and/or trolox were administered orally at a dosage of 20 mg/kg/day to CFA-induced arthritic rats for 2 weeks. The normal and arthritic control groups were orally given the same equivalent volume of a vehicle (1% carboxymethyl cellulose) in which treatment agents were dissolved. At the end of the experiment, blood samples were collected from the jugular vein for the detection of the total leukocyte count (TLC) and differential leukocyte count (DLC) in blood and the detection of rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), tumor necrosis factor-α (TNF-α), interleukin-13 (IL-13), and interleukin-17 (IL-17) levels by enzyme-linked immunosorbent assay (ELISA), as well as markers of oxidative stress and the antioxidant defense system in serum. The right hind ankle regions of three rats from each group were dissected out and fixed in 10% neutral-buffered formalin for histological examination and the other three were kept at −30 °C for Western blot analysis of nuclear factor-kappa B (NF-κB) protein 50 (NF-κB p50), NF-κB p65, inducible nitric oxide synthase (iNOS), nuclear factor erythroid-2-related factor 2 (Nrf2), and matrix metalloproteinase (MMP)-1 (MMP-1), MMP-3, and MMP-9. The CFA injection was deleterious to the ankle joint’s histological architecture, manifesting as infiltration of inflammatory cells into the articular cartilage, hyperplasia of the synovium, and erosion of the cartilage. All these effects were ameliorated by diosmin and/or trolox, with the combined dose being the most effective. The two compounds significantly lowered the elevated serum levels of RF, ACPA, TNF-α, and IL-17, as well as other pro-inflammatory mediators, such as NF-κB p50, NF-κB p65, iNOS, MMP-1, MMP-3 and MMP-9. They also increased the levels of the anti-inflammatory cytokine, IL-13, and the cytoprotective transcription factor Nrf2. The compounds stimulated higher activities of antioxidants, such as glutathione, glutathione-S-transferase, catalase, and superoxide dismutase, and reduced lipid peroxidation in the serum of arthritic rats. In conclusion, diosmin, trolox, and their combination, which was the most potent, exerted anti-arthritic, anti-inflammatory and antioxidant effects by suppressing NF-κB signaling, inhibiting matrix metalloproteinases, and activating Nrf2.

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“…In a mouse oral QUE model and H9c2 cells, QUE was found to reduce oxidative stress and myocardial apoptosis by downregulating p53 and NADPH oxidase 1 [ 137 ]. The combination of QUE and DOX also provided p53-related hepatoprotective effects to the liver and immune system in a rat model [ 138 , 139 ].…”

Section: Nutrients Can Attenuate Dox Toxicity and Drug Resistance By ...mentioning

confidence: 99%

p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act

Guo

Tang²,

et al. 2023

Nutrients

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Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.

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Rutin and Quercetin Counter Doxorubicin-Induced Liver Toxicity in Wistar Rats via Their Modulatory Effects on Inflammation, Oxidative Stress, Apoptosis, and Nrf2

Cited by 36 publications

References 82 publications

Protective effects of metformin against doxorubicin-induced hepatoxicity in rats

Protective effects of metformin against doxorubicin-induced hepatoxicity in rats

Diosmin and Trolox Have Anti-Arthritic, Anti-Inflammatory and Antioxidant Potencies in Complete Freund’s Adjuvant-Induced Arthritic Male Wistar Rats: Roles of NF-κB, iNOS, Nrf2 and MMPs

p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act

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